Prior to the widespread use of highly active anti-retroviral therapy (HAART) roughly 20% of HIV-infected patients developed HIV-associated dementia (HAD). HAART has clearly decreased the incidence of HAD, but its prevalence, or that of less severe cognitive disorders, may rise as individuals with HIV infection live longer. Lentiviral encephalitis also occurs consistently in macaques infected with simian immunodeficiency virus (SIV), the most important animal model for HIV. Studies that have analyzed viral genotypes at later points have also established that there is clear genetic divergence between viruses harbored within the brain and the spleen and other peripheral tissue of the same individual, regardless of the portion of the genome that is analyzed. In some instances regional variation within the CNS has also been documented. However it is not clear (1) whether the brain genotypes arise as a result of adaptive selection, decreased immunological constraints due to the brain's 'privileged' position with respect to the immune system, or are due to genetic drift of a compartmentalized population. Alternatively it could be a confluence of all these factors. It is also uncertain (2) whether the variants developing within the brain may be particularly neuropathogenic, and (3) whether the variants within the brain constitute a potential reservoir of latent infection, able to re-seed the systemic circulation after treatment with HAART. We propose to address these questions using simian immunodeficiency virus (SIV) infection of rhesus macaques, a model that recapitulates most of the features of HIV infection including CNS disease. We propose three specific aims. In the first aim, we will amplify and clone env genomic DNA from macaques with SIV encephalitis, compare the genomic DNA with SIV RNA amplified from individual multinucleated giant cells, and assay the envelopes functionally and for their neuropathogenic potential. In the second specific aim, we will analyze blood, cerebrospinal fluid and other tissues in macaques infected with a molecular clone of SIV, to determine the time course of compartmentalization of SIV within the CNS. In the third specific aim we will follow up on previous results indicating that some cells harbor SIV sequences for periods as long as 2 years. These experiments will help clarify the role of genetic sequestration in the development of SIV encephalitis, and by extension, in its human counterpart. [unreadable] [unreadable]